Pancreatic cancer is a lethal disease and a significant cause of cancer deaths worldwide. In the US, pancreatic cancer is one of the few cancers where the death rate has risen since 1990, and it is currently the 4th leading cause of cancer-related deaths. Furthermore, this cancer is difficult to detect until the disease has reached an advanced stage, when available treatments are not effective, as these tumors are often resistance to chemotherapies. The poor prognosis and drug resistance of this devastating disease demonstrate the urgent need for new forms of diagnosis and treatment. When properly stimulated, the human immune system has the ability to kill cancer cells, which makes immunotherapies a promising avenue in the fight against cancer. To trigger an anti-cancer immune response, the effector cells of the immune system, known as T cells, must recognize signals on cancer cells through molecules called T cell receptors. The human immune system is naturally equipped to recognize only a certain set of signals that are often weakly recognized by their corresponding T cell receptors. Therefore, the focus of this project is to genetically engineer T cells with a new T cell receptor that can recognize signals on pancreatic cancer cells that the human immune system does not naturally recognize. These engineered T cells would hence act as a superior way for T cells to recognize and kill pancreatic cancer cells, and could be used directly to successfully treat pancreatic cancer patients, potentially even those with advanced stages of the disease when current treatments are unsuccessful. Furthermore, this project utilizes innovative techniques to engineer biologics to enhance T cell therapies. Through a process known as `click chemistry' developed in the Ploegh lab, I will produce biologically active molecules that can lift the brakes off the immune system, either in a dualistic manner or in a tumor-site-specific manner, and that can attract effector T cells to tumors to increase their ability to kill cancer cells. Taken together, this proposal utilizes many innovative techniques to target multiple levels of pancreatic cancer that could be broadly applicable to T cell therapies fo many other human malignancies. The completion of this project, and mastery of the cutting-edge techniques utilized herein will represent a major step in my development as an independent cancer researcher.